Frontal deficits and atrophy in a patient with familial encephalopathy with neuroserpin inclusion bodies detected by single-case voxel-based morphometry: a case report.

BACKGROUND: Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare genetic disorder characterized by progressive cognitive decline and myoclonic epilepsy, caused by pathogenic variants of SERPINI1. We reported a case of genetically confirmed FENIB with de novo H338R mutation in the SERPINI1, in which frontal deficits including inattention and disinhibition, and relevant atrophy in the vmPFC on brain MRI were observed in the early stage of the disease. CASE PRESENTATION: A 23-year-old Japanese man presented with progressive inattention and disinhibition over 4 years followed by myoclonic epilepsy. The whole-genome sequencing and filtering analysis showed de novo heterozygous H338R mutation in the SERPINI1, confirming the diagnosis of FENIB. Single-case voxel-based morphometry using brain magnetic resonance imaging obtained at the initial visit revealed focal gray matter volume loss in the ventromedial prefrontal cortices, which is presumed to be associated with inattention and disinhibition. CONCLUSION: Frontal deficits including inattention and disinhibition can be the presenting symptoms of patients with FENIB. Single-case voxel-based morphometry may be useful for detecting regional atrophy of the frontal lobe in FENIB. Detecting these abnormalities in the early stage of disease may be key findings for differentiating FENIB from other causes of progressive myoclonic epilepsy.

Morphometry and network-based atrophy patterns in SCN1A-related Dravet syndrome.

Mutations of the voltage-gated sodium channel SCN1A gene (MIM#182389) are among the most clinically relevant epilepsy-related genetic mutations and present variable phenotypes, from the milder genetic epilepsy with febrile seizures plus to Dravet syndrome, a severe developmental and epileptic encephalopathy. Qualitative neuroimaging studies have identified malformations of cortical development in some patients and mild atrophic changes, partially confirmed by quantitative studies. Precise correlations between MRI findings and clinical variables have not been addressed. We used morphometric methods and network-based models to detect abnormal brain structural patterns in 34 patients with SCN1A-related epilepsy, including 22 with Dravet syndrome. By measuring the morphometric characteristics of the cortical mantle and volume of subcortical structures, we found bilateral atrophic changes in the hippocampus, amygdala, and the temporo-limbic cortex (P-value < 0.05). By correlating atrophic patterns with brain connectivity profiles, we found the region of the hippocampal formation as the epicenter of the structural changes. We also observed that Dravet syndrome was associated with more severe atrophy patterns with respect to the genetic epilepsy with febrile seizures plus phenotype (r = -0.0613, P-value = 0.03), thus suggesting that both the underlying mutation and seizure severity contribute to determine atrophic changes.

Familial adult myoclonus epilepsy: Neuroimaging and neuropathological findings.

Familial adult myoclonus epilepsy (FAME) is characterized by cortical myoclonus and often epileptic seizures, but the pathophysiology of this condition remains uncertain. Here, we review the neuroimaging and neuropathological findings in FAME. Imaging findings, including functional magnetic resonance imaging, are in line with a cortical origin of involuntary tremulous movements (cortical myoclonic tremor) and indicate a complex pattern of cerebellar functional connectivity. Scarce neuropathological reports, mainly from a single family, provide evidence of morphological changes in the Purkinje cells. Cerebellar changes seem to be part of the syndrome, in at least some FAME pedigrees. Cortical hyperexcitability in FAME, resulting in the cardinal clinical symptoms, might be the result of decreased cortical inhibition via the cerebellothalamocortical loop. The pathological findings might share some similarities with other pentanucleotide repeat disorders. The relation with genetic findings in FAME needs to be elucidated.

Altered cerebellar-motor loop in benign adult familial myoclonic epilepsy type 1: The structural basis of cortical tremor.

OBJECTIVE: Cortical tremor/myoclonus is the hallmark feature of benign adult familial myoclonic epilepsy (BAFME), the mechanism of which remains elusive. A hypothesis is that a defective control in the preexisting cerebellar-motor loop drives cortical tremor. Meanwhile, the basal ganglia system might also participate in BAFME. This study aimed to discover the structural basis of cortical tremor/myoclonus in BAFME. METHODS: Nineteen patients with BAFME type 1 (BAFME1) and 30 matched healthy controls underwent T1-weighted and diffusion tensor imaging scans. FreeSurfer and spatially unbiased infratentorial template (SUIT) toolboxes were utilized to assess the motor cortex and the cerebellum. Probabilistic tractography was generated for two fibers to test the hypothesis: the dentato-thalamo-(M1) (primary motor cortex) and globus pallidus internus (GPi)-thalamic projections. Average fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) of each tract were extracted. RESULTS: Cerebellar atrophy and dentate nucleus alteration were observed in the patients. In addition, patients with BAFME1 exhibited reduced AD and FA in the left and right dentato-thalamo-M1 nondecussating fibers, respectively false discovery rate (FDR) correction q < .05. Cerebellar projections showed negative correlations with somatosensory-evoked potential P25-N33 amplitude and were independent of disease duration and medication. BAFME1 patients also had increased FA and decreased MD in the left GPi-thalamic projection. Higher FA and lower RD in the right GPi-thalamic projection were also observed (FDR q < .05). SIGNIFICANCE: The present findings support the hypothesis that the cerebello-thalamo-M1 loop might be the structural basis of cortical tremor in BAFME1. The basal ganglia system also participates in BAFME1 and probably serves a regulatory role.

Aberrant visual-related networks in familial cortical myoclonic tremor with epilepsy.

INTRODUCTION: In familial cortical myoclonic tremor with epilepsy, photic stimulation can trigger visual symptoms and induce a photoparoxysmal response, or photosensitivity, on electroencephalography. However, the mechanism is poorly understood. In this study, we aimed to explore the neuroimaging changes related to visual symptoms and photosensitivity in genetically confirmed familial cortical myoclonic tremor with epilepsy type 1. METHODS: Resting-state functional magnetic resonance imaging and electroencephalography data were collected from 31 patients carrying the heterozygous pathogenic intronic pentanucleotide (TTTCA)n insertion in the sterile alpha motif domain-containing 12 gene and from 52 age- and sex-matched healthy controls. RESULTS: (1) Both regional homogeneity and degree centrality values in the bilateral calcarine sulcus were significantly increased in patients compared with healthy controls. (2) When the calcarine sulcus area with increased regional homogeneity was taken as a seed, increased functional connectivity values were observed in the right precentral gyrus, while decreased functional connectivity values were observed in the right superior frontal gyrus and right inferior parietal lobule. (3) Independent component analysis showed increased connectivity in the left calcarine sulcus inside the medial visual network. (4) Correlation analysis revealed a significant positive correlation between regional homogeneity values and frequency of seizure, and photoparoxysmal response grades were positively correlated with the severity of cortical tremor and duration of epilepsy. CONCLUSION: These findings provide strong evidence for the interpretation of visual symptoms and photosensitivity in familial cortical myoclonic tremor with epilepsy. We speculate that functional changes in the primary visual cortex may be an imaging biomarker for the disease.

Long-term cardiovascular safety of fenfluramine in patients with Dravet syndrome treated for up to 3 years: Findings from serial echocardiographic assessments.

OBJECTIVE: To assess the cardiovascular safety of fenfluramine when used to treat children and young adults with Dravet syndrome. METHODS: Patients with Dravet syndrome who completed one of three phase 3 clinical trials of fenfluramine could enroll in the open-label extension (OLE) study (NCT02823145). All patients started fenfluramine treatment at an oral dose of 0.2 mg/kg/day. The dose was titrated based on efficacy and tolerability to a maximum of 0.7 mg/kg/day (absolute maximum 26 mg/day) or 0.4 mg/kg/day (absolute maximum 17 mg/day) in patients concomitantly receiving stiripentol. Serial transthoracic echocardiography was performed using standardized methods and blinded readings at OLE entry, after 4-6 weeks, and every 3 months thereafter. Valvular heart disease (VHD) was defined as ≥ moderate mitral regurgitation or ≥ mild aortic regurgitation combined with physical signs or symptoms attributable to valve dysfunction. Pulmonary artery hypertension (PAH) was defined as systolic pulmonary artery pressure >35 mmHg. RESULTS: A total of 327 patients (median age, 9.0 years; range, 2-19 years) have enrolled in the OLE and received ≥1 dose of fenfluramine. The median duration of treatment was 23.9 months (range, 0.2-42.6 months) and the median dose of fenfluramine was 0.44 mg/kg/day. No patient demonstrated VHD or PAH at any time during the OLE. SIGNIFICANCE/INTERPRETATION: This study, which represents the largest, longest, and most rigorous examination of cardiovascular safety of fenfluramine yet reported, found no cases of VHD or PAH. These results, combined with fenfluramine's substantial antiseizure efficacy, support a strong positive benefit-risk profile for fenfluramine in the treatment of Dravet syndrome.

Dravet syndrome with parkinsonian symptoms and intact dopaminergic neurons: A case report.

INTRODUCTION: Dravet syndrome (DS) is severe myoclonic epilepsy in infancy and associated with a heterozygous mutation of the gene for the sodium channel alpha 1 subunit (SCN1A). Recently, adult patients with DS have been reported to show parkinsonism, but no corresponding neuroimaging data are available. Here, we present neuroimaging data in 2 adult patients with DS showing parkinsonian symptoms. CASE REPORT: Case 1: A man who had intractable seizures from the age of 1 year and 2 months was diagnosed with DS at 7 with a mutation in the SCN1A gene. At 18, he had parkinsonian symptoms such as masked face and bradykinesia. At 20, he was admitted to our department. Dopamine transporter single-photon emission computed tomography (DAT SPECT) showed no decrease in striatal binding of 123I-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane (123I-FP-CIT), and myocardial scintigraphy showed no decrease in cardiac uptake of 123I-metaiodobenzylguanidine (123I-MIBG). Levodopa showed no significant improvement in his symptoms. Case 2: A woman who had febrile seizures at 4 months of age and myoclonic seizures at 1 year and 5 months was diagnosed with DS at 31. She had myoclonus, resting tremor, hypertonia, antecollis, crouch gait, and bradykinesia. DAT SPECT imaging showed no decrease in striatal FP-CIT binding, and levodopa did not improve her symptoms. DISCUSSION: The normal DAT SPECT and 123I-MIBG results suggest that dopaminergic neurons projecting onto striatal neurons were not impaired in our patients, explaining the lack of response to levodopa. Thus, dopamine imaging can help to guide treatment decisions in patients with DS and parkinsonism.

EEG abnormalities in patients with chronic neuronopathic Gaucher disease: A retrospective review.

The clinical phenotype of Gaucher disease type 3 (GD3), a neuronopathic lysosomal storage disorder, encompasses a wide array of neurological manifestations including neuro-ophthalmological findings, developmental delay, and seizures including progressive myoclonic epilepsy. Electroencephalography (EEG) is a widely available tool used to identify abnormalities in cerebral function, as well as epileptiform abnormalities indicating an increased risk of seizures. We characterized the EEG findings in GD3, reviewing 67 patients with 293 EEGs collected over nearly 50 years. Over 93% of patients had some form of EEG abnormality, most consisting of background slowing (90%), followed by interictal epileptiform discharges (IEDs) (54%), and photoparoxysmal responses (25%). The seven patients without background slowing were all under age 14 (mean 6.7 years). There was a history of seizures in 37% of this cohort; only 30% of these had IEDs on EEG. Conversely, only 56% of patients with IEDs had a history of seizures. These observed EEG abnormalities document an important aspect of the natural history of GD3 and could potentially assist in identifying neurological involvement in a patient with subtle clinical findings. Additionally, this comprehensive description of longitudinal EEG data provides essential baseline data for understanding central nervous system involvement in neuronopathic GD.

Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.

OBJECTIVE: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. METHODS: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. RESULTS: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. SIGNIFICANCE: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: Analysis of an ongoing long-term open-label safety extension study.

OBJECTIVE: Fenfluramine, which was previously approved as a weight loss drug, was withdrawn in 1997 when reports of cardiac valvulopathy emerged. The present study was conducted in part to characterize the cardiovascular safety profile of low-dose fenfluramine when used in a pediatric population to reduce seizure frequency in patients with Dravet syndrome. METHODS: Patients 2- to 18-years-old with Dravet syndrome who had completed any of three randomized, placebo-controlled clinical trials of fenfluramine were offered enrollment in this open-label extension (OLE) study. All patients were treated with fenfluramine starting at a dose of 0.2 mg/kg/day (oral solution dosed twice per day), which was titrated to maximal effect with a dose limit of 0.7 mg/kg/day (maximum 26 mg/day) or 0.4 mg/kg/day (maximum 17 mg/day) in patients receiving concomitant stiripentol. Standardized echocardiographic examinations were conducted at Week 4 or 6 and then every 3 months during the OLE study to monitor cardiac valve function and structure and pulmonary artery pressure. The primary end point for the echocardiography analysis was the number of patients who developed valvular heart disease or pulmonary artery hypertension (PAH) during treatment. RESULTS: A total of 232 patients were enrolled in the study. The average age of patients was 9.1 ± 4.7 years, and 55.2% were male. The median duration of treatment with fenfluramine was 256 days (range = 58-634 days), and the mean dose of fenfluramine was 0.41 mg/kg/day. No cases of valvular heart disease or PAH were observed. SIGNIFICANCE: Longitudinal echocardiography over a median 8.4 months of treatment with fenfluramine suggests a low risk of developing cardiac valvulopathy and PAH when used to treat pediatric patients with Dravet syndrome.

Molecular diagnosis of epileptic encephalopathy of the first year of life applying a customized gene panel in a group of Argentinean patients.

OBJECTIVE: The aim of this study was to perform a molecular characterization of 17 Argentinean pediatric patients with diagnosis of having epileptic encephalopathies (EEs) of the first year of life without known etiology, applying next-generation sequencing (NGS). METHODS: We included 17 patients with EE with age of onset under 12 months without known etiology after ruling out structural abnormalities, metabolic disorders, and large chromosomal abnormalities. They presented with the following clinical phenotypes: Dravet syndrome (DS; n: 7), epilepsy of infancy with migrating focal seizures (EIMFS; n: 3), West syndrome (WS; n: 2), and undetermined epileptic encephalopathy (UEE; n: 5). Neurologic examinations, seizure semiology, brain magnetic resonance imaging, and standard electroencephalography (EEG) or video-EEG studies were performed in all cases. Using a custom amplicon strategy, we designed an NGS panel to study 47 genes associated with EEs. RESULTS: Pathogenic variants were detected in 8 cases (47%), including seven novel pathogenic variants and one previously reported as being pathogenic. The pathogenic variants were identified in 6 patients with DS (SCN1A gene), one with EIMFS (SCN2A gene), and one with UEE (SLC2A1 gene). Nonrelevant variants were identified in the patients with WS. CONCLUSION: We demonstrated the feasibility of an NGS-gene panel approach for the analysis of patients with EE in our setting. A genetic diagnosis was achieved in nearly 50% of patients, 87% of them presenting with nonpreviously reported variants. The early identification of the underlying causative genetic alteration will be a valuable tool for providing prognostic information and genetic counselling and also to improve therapeutic decisions in Argentinean patients.

Altered Cerebello-Motor Network in Familial Cortical Myoclonic Tremor With Epilepsy Type 1.

BACKGROUND: Intronic pentanucleotide insertion in the sterile alpha motif domain-containing 12 gene was recently identified as the genetic cause of familial cortical myoclonic tremor with epilepsy type 1. OBJECTIVES: We thereafter conducted a multimodal MRI research to further understand familial cortical myoclonic tremor with epilepsy type 1. METHODS: We enrolled 31 patients carrying heterozygous pathogenic intronic pentanucleotide insertion in the sterile alpha motif domain-containing 12 gene and 31 age- and sex-matched healthy controls. We compared multimodal MRI metrics, including voxel-based morphometry, fractional anisotropy of diffuse tensor imaging, frequency-dependent percent amplitude fluctuation, and seed-based functional connectivity of resting-state functional MRI. RESULTS: Significant decreased gray matter volume was found in the cerebellum. Percent amplitude fluctuation analysis showed significant interaction effect of "Frequency by Group" in three regions, including the vermis VIII, left cerebellar lobule VIII, and left precentral gyrus. Specifically, the lowest-frequency band exhibited significant increased percent amplitude fluctuation in patients in the two cerebellar subregions, whereas the highest-frequency band exhibited decreased percent amplitude fluctuation in the precentral gyrus in patients. Discriminative analysis by support vector machine showed a mean accuracy of 82% (P = 1.0-5 ). An increased functional connectivity between vermis VIII and the left precentral gyrus was found in patients with familial cortical myoclonic tremor with epilepsy type 1. A positive correlation between the percent amplitude fluctuation in the left cerebellar lobule VIII and duration of cortical tremor was also found. CONCLUSION: The cerebellum showed both structural and functional damages. The distinct change of spontaneous brain activity, that is, increased ultra-low-frequency amplitude in the cerebellum and the decreased higher-frequency amplitude in the motor cortex, might be a pathophysiological feature of familial cortical myoclonic tremor with epilepsy type 1. © 2020 International Parkinson and Movement Disorder Society.

Variants in NGLY1 lead to intellectual disability, myoclonus epilepsy, sensorimotor axonal polyneuropathy and mitochondrial dysfunction.

NGLY1 encodes the enzyme N-glycanase that is involved in the degradation of glycoproteins as part of the endoplasmatic reticulum-associated degradation pathway. Variants in this gene have been described to cause a multisystem disease characterized by neuromotor impairment, neuropathy, intellectual disability, and dysmorphic features. Here, we describe four patients with pathogenic variants in NGLY1. As the clinical features and laboratory results of the patients suggested a multisystem mitochondrial disease, a muscle biopsy had been performed. Biochemical analysis in muscle showed a strongly reduced ATP production rate in all patients, while individual OXPHOS enzyme activities varied from normal to reduced. No causative variants in any mitochondrial disease genes were found using mtDNA analysis and whole exome sequencing. In all four patients, variants in NGLY1 were identified, including two unreported variants (c.849T>G (p.(Cys283Trp)) and c.1067A>G (p.(Glu356Gly)). Western blot analysis of N-glycanase in muscle and fibroblasts showed a complete absence of N-glycanase. One patient showed a decreased basal and maximal oxygen consumption rates in fibroblasts. Mitochondrial morphofunction fibroblast analysis showed patient specific differences when compared to control cell lines. In conclusion, variants in NGLY1 affect mitochondrial energy metabolism which in turn might contribute to the clinical disease course.

Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: Identification of a new KCND3 phenotype and novel genes causing Dravet syndrome.

PURPOSE: This study aimed to investigate the genetic etiology of epilepsy in a cohort of Chinese children. METHODS: Targeted next-generation sequencing (NGS) was performed for 120 patients with unexplained epilepsy, including 71 patients with early-onset epileptic encephalopathies, and 16 patients with Dravet syndrome (including three patients with a Dravet-like phenotype) but without SCN1A pathogenic variants. RESULTS: Pathogenic variants of 14 genes were discovered in 22 patients (18%). A de novo KCND3 pathogenic variant (c.1174G > A, p.Val392Ile) was identified in a boy with refractory epilepsy, psychomotor regression, attention deficit, and visual decline. Pathogenic variants in other coding genes were excluded via whole exome sequencing. This KCND3 variant was previously confirmed to be pathogenic by Giudicessi, et al. However, the clinical profile was different: sudden death at 20 years old without any medical history of neurological disorders, nor with any diseases typically caused by KCND3 pathogenic variants such as Brugada syndrome, spinocerebellar ataxia type 19/22 or ataxia accompanied by epilepsy. This indicates that we have identified a new KCND3 phenotype. In addition, we also uncovered a GRIN1 pathogenic variant and a novel HCN1 pathogenic variant in the Dravet cohort. CONCLUSION: Our study highlights the significant utility of NGS panels in the genetic diagnosis of pediatric epilepsy. Our findings indicate that KCND3 pathogenic variants may be responsible for a wider phenotypic spectrum than previously thought, by including childhood epileptic encephalopathy. Furthermore, this study provides evidence that GRIN1 and HCN1 are candidate genes for Dravet and Dravet-like phenotypes.

Elimination of amyloid precursor protein in senile plaques in the brain of a patient with Alzheimer-type dementia and Down syndrome.

The average lifespan of individuals with Down syndrome has approximately doubled over the past three decades to 55-60 years. To reveal the pathogenic process of Alzheimer-type dementia in individuals with Down syndrome, we immunohistochemically examined senile plaque formation in the cerebral cortex in the autopsy brain and compared findings with our previous studies. We described a 52-year-old female with Down syndrome who developed progressively more frequent myoclonus following cognitive decline and died at the age of 59 years. Her karyotype [46XX, inv(9)(p12q13), i(21)(q10)] included triplication of the gene for amyloid precursor protein and the Down syndrome critical region. On microscopy, very few gamma-aminobutyric acid-ergic (GABAergic) neurons, in the form of small granular cells, in the cortex and Purkinje cells in the cerebellum were visible. In our previous study, amyloid precursor protein immunoreactivity was first noted in senile plaques at the age of 32 years. In this patient, even though amyloid ß immunoreactivity was detected in the cores of senile plaques and diffuse plaques, amyloid precursor protein immunoreactivity was not noted in senile plaques in the frontal cortex. Amyloid precursor protein and its derivative amyloid-ß play an important role in the formation of senile plaques and the time course of immunoreactive expression may be related to the pathogenic process of Alzheimer-type dementia.

Progressive myoclonus epilepsy and ceroidolipofuscinosis 14: The multifaceted phenotypic spectrum of KCTD7-related disorders.

BACKGROUND: Mutations in the KCTD7 gene have been associated with progressive myoclonus epilepsy and, in a single patient, with the so-called "Neuronal Ceroid Lipofuscinosis 14" (characterised by myoclonic seizures, cognitive regression, optic atrophy leading to visual loss, and progressive cortical and cerebellar atrophy). CLINICAL REPORTS: We describe two new patients carrying two novel pathogenic mutations in the KCTD7 gene. Patient 1 (NM_153033.4: c.[533C > T], NP_694578: p.[(Ala178Val)]) was a 17-year-old girl who presented with early-onset epilepsy resembling epilepsia partialis continua (responsive to intravenous corticosteroids and immunoglobulins), and later developed myoclonic seizures and atypical absences, photosensitivity to very low frequencies and progressive seizures-related neurocognitive and motor deterioration. Patient 2 (NM_153033.4: c.[172G>A], NP_694578: p.[(Gly58Arg)]) presented with early neurological regression, myoclonic seizures and lysosomal storage material which was consistent with a neuronal ceroid lipofuscinosis (NCL) at skin biopsy. Both patients had non epileptic myoclonus. CONCLUSIONS: The two reported patients carrying novel pathogenic variants in KCTD7 gene presented with a remarkable phenotypic heterogeneity including: a) progressive myoclonus epilepsy without NCL-type lysosomal storages; b) progressive myoclonus epilepsy with lysosomal storages resembling NCL pattern (NCL14); c) progressive myoclonus epilepsy with epilepsia partialis continua.

Antimyoclonic Effect of Levetiracetam and Clonazepam Combined Treatment on Myoclonic Epilepsy with Ragged-Red Fiber Syndrome with m.8344A>G Mutation.

BACKGROUND: Treatment of myoclonic seizures in myoclonic epilepsy with ragged-red fibers (MERRFs) has been empirical and ineffective. Guideline on this disease is not available. Additional trials must be conducted to find more suitable treatments for it. In this study, the antimyoclonic effects of monotherapies, including levetiracetam (LEV), clonazepam (CZP), valproic acid (VPA), and topiramate (TPM) compared to combination therapy group with LEV and CZP on MERRF, were evaluated to find a more advantageous approach on the treatment of myoclonic seizures. METHODS: Treatments of myoclonic seizures with VPA, LEV, CZP, and TPM were reported as monotherapies in 17 MERRF patients from Qilu Hospital between 2003 and 2016, who were diagnosed through clinical data and genetic testing. After 1-4 months of follow-up (mean: 82.9 ± 28.1 days), 12 patients that exhibited poor responses to monotherapy were given a combined treatment consisting of LEV and CZP subsequently. The follow-up period was 4-144 months (mean: 66.3 ± 45.3 months), the effective rates of monotherapy group (17 patients) and combination therapy group (12 patients) were analyzed by Chi-square test. RESULTS: The m.8344 A>G mutation was detected in all patients. There were four patients with partial response (4/17, two in the CZP group and two in the LEV group), ten patients with stable disease (10/17, six in the CZP group, three in the LEV group, and one in the TPM group), and three patients with progressive disease (3/18, two in the VPA group and one in the TPM group). Twelve of the patients with LEV combined with CZP showed a positive effect and good tolerance (12/12), eight of them demonstrated improved cognition and coordination. There was a significant difference between the monotherapy group and combination therapy group in the efficacy of antimyoclonic seizures (χ2 = 13.7, P < 0.001). CONCLUSIONS: LEV in combination with CZP is an efficient and safe treatment for myoclonic seizures in patients with this disease exhibiting the m.8344A>G mutation.

[18F]fluorodeoxyglucose-positron emission tomography study of genetically confirmed patients with Dravet syndrome.

OBJECTIVE: To understand cerebral brain dysfunction in patients with Dravet syndrome (DS), we conducted a [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) study in patients with DS whose SCN1A gene variant was confirmed. METHODS: FDG-PET was performed on eight patients with DS. A SCN1A mutation analysis revealed missense variants in four patients and truncation variants in four patients. The patients' ages at the time of the PET study were 2, 2, 2, 3, 6, 13, 20, and 29 years old, respectively. The patients' developmental/intelligence quotient at the time of the PET study were 62, 52, 64, 35, 30, 15, and <25, respectively. The mean standardized uptake value (SUV) was calculated in four segments (frontal, temporal, parietal, and occipital) for the semi-quantitative analysis of 18F-FDG uptake. This value represents the average of the regions of interest in each lobe and was divided by the average SUV of the cerebellar hemisphere of each patient and compared between the patients with DS and the diseased controls. RESULTS: Glucose uptake in patients with DS decreased significantly, particularly in those ≥6 years old. Importantly, a comparison between the younger and older patients with DS revealed that glucose uptake was normal in patients who were ≤3 years (2, 2, 2, and 3 years), whereas a profound reduction in glucose uptake in the fronto-temporo-parietal-occipital cortices was observed in patients ≥ 6 years (6, 13, 20, and 29 years). Magnetic resonance imaging revealed no detectable atrophic legions or other changes in the cerebral cortices of patients ≥ 6 years of age. SIGNIFICANCE: The present study showed a remarkable reduction in cerebral glucose metabolism in multiple lobes for the first time, which became obvious after the late infantile period. These findings may indicate a functional neuroimaging aspect of epileptic encephalopathy of DS or a feature of the SCN1A variant itself.

Early-onset epileptic encephalopathy with myoclonic seizures related to 9q33.3-q34.11 deletion involving STXBP1 and SPTAN1 genes.

We describe a 10-month-old boy with early-onset epileptic encephalopathy who was found to have a hemizygous deletion in 9q33.3-q34.11 involving STXBP1 and SPTAN1 genes. He presented at the age of 2.5 months with frequent upper extremity myoclonus, hypotonia, and facial dysmorphisms. Interictal EEG showed multifocal polyspike and wave during wakefulness and sleep. Ictal EEG revealed low-amplitude generalized sharp slow activity, followed by diffuse attenuation. Metabolic testing was unrevealing. Brain MRI showed thinning of the corpus callosum with an absence of rostrum. This patient is the second reported case with 9q33.3-q34.11 deletion involving STXBP1 and SPTAN1 genes associated with epileptic encephalopathy and myoclonic seizures. Larger case series are needed to better delineate this association.